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Friedreich's Ataxia

Last edited on January 2, 2016 by Timothy C. Hain, MD, Chicago Dizziness and Hearing.

Friedreich's ataxia (FA), first described by Nicholaus Friedreich in 1863, was thought to be the most common inherited ataxia, before FXTAS was discovered. Friedreichs is transmitted with autosomal recessive inheritance. It's estimated prevalence in European populations is 1 in 50,000. It is associated with a mutation that consists of unstable expansion of GAA repeats on chromosome 9. The repeat expansion causes a transcriptional defect of the fratxin gene, a small mitochondrial protein, that is responsible for all of the clinical manifestations of FA (Durr et al, 1996).  As the number of repeats is variable, the severity of the condition is also variable.

Considering all cases of inherited ataxia, FA alleles were found in about 11.4% of apparently recessive and 5.2% of apparently sporadic patients (Moseley et al, 1998).

An immense amount of work on FrA was led by Dr. Adrian Barbeau, in Quebec, Canada. The validity of their studies as well as other older ones is somewhat suspect as this work was done prior to genetic characterization of the disorder.

The mechanism for the majority of the findings in Freidreichs is degeneration of sensory ganglia -- i.e. deafferentation of the cerebellum.

Clinical picture:

Onset of symptoms is usually before 20 years of age (15 +- 8). There is ataxia of all four limbs associated with cerebellar dysarthria, absent reflexes in the lower limbs, sensory loss and pyramidal signs (Durr et al, 1996).  Knee jerks are rarely present, and vibration sensation is usually absent.

Hypertrophic concentric cardiomyopathy is found in a majority of patients. Skeletal deformities and abnormalities in glucose metabolism are common. Other associated but unusual findings may be facial dysmorphia, myoclonus, dystonia, postural tremor, supranuclear gaze paresis, and mental retardation (Durr et al, 1996)

It is strange that there should be eye movement abnormalities in FA, as the pathology of FA is sensory ganglion degeneration, and the eyes are not thought to have any substantial sensory input regarding position.  Nevertheless, according to Ell, Prasher and Ruge (1984), there are impairments of saccadic accuracy, square wave jerks, ocular flutter, rebound nystagmus, and impaired pursuit. This was an older study, done prior to genetic characterization of FA, and they may actually have been studying another disease. At roughly the same time (1983), Furman and  others reported a similar symptom complex of fixation instability, inaccurate saccades, impaired smooth pursuit, and decreased VOR gain. Again, it is difficult to know if these patients truly had FA, as this is an older study. In the well characterized population of Durr (1996), horizontal nystagmus was found in 40%, and saccadic pursuit in 30%.  In our opinion, these findings are both subjective and common ones in otherwise normal persons, possibly taking medications for sleep or drinking alcohol. In other words, we are dubious that there are substantial eye movement abnormalities in Friedreichs.

Hearing loss was reported in only 13% of Durr's patients (1996). Spoendlin commented that two had "peaked" audiograms.  Nevertheless, abnormal auditory evoked responses are found in about 50% of patients, and the auditory neuropathy syndrome has been reported in this disease. It seems reasonable that there might be more abnormal ABR's in this disorder than hearing loss, although it does not appear to be causing substantial damage. According to Satya-Murti et al (1980), hearing disturbance is associated with spiral ganglion degeneration.  This is thus another sensory ganglion that degenerates.   We do not see why there should be any selectivity to the hearing loss, and do not understand the observations of Spoendlin (e.g. perhaps they are wrong).

One would expect that the vestibular ganglion might also degenerate in Friedreichs, and pathological studies have suggested that this is the case.  A similar situation is found in the CANVAS syndrome, which is very similar to Friedreichs except it has more vestibular disturbance. (Szmulewicz et al, 2011)

Prognosis

In patients homozygous for GAA expansion, the mean time to wheelchair confinement averages 10.8 years, and the mean disease duration is 15+-9 years. (Cosee et al, 1999). Death often occurs due to the cardiomyopathy (see below).

Pathology:

The pathology of FA is largely confined to the dorsal root ganglion. Cerebellar neurons are usually normal but there are also lesions in the dentate nucleus. There are also effects on the heart, skeleton and endocrine pancreas. Temporal bones from patients with Freidreichs have shown spiral ganglion and Scarpa's ganglion cell degeneration (Merchant et al, 2001).  

About 2/3 of FA patients have a cardiomyopathy, and most patients eventually succumb to it (Bidichandani et al, 1993). Pousset et al (2015) reported in their 15 patients who died, 80% died of cardiac causes.

Many become diabetic during their life (Koeppen AH, 2011).

Treatment:

Little treatment is available other than supportive care, but there are a few trials

Current thought is that there is no agent that has a significantly positive effect.

Genetics

The following is just a brief discussion of how autosomal recessive inheritance works.  It is not meant to substitute for genetic counseling.

FA is almost always a autosomal recessive disease. Generally speaking then, all children of persons with FA are FA carriers. They cannot develop FA themselves as long as their other parrent is not also a carrier. As the frequency of FA is 1/50,000 in the general population, the chance of encountering another carrier in a spouse is roughly 1/200. When a homozygote for a recessive disorder marries a carrier, the chance of children being affected is 50%. Thus, the chance that a person with FA's children will also have FA is about 1/400.

Should two carriers marry, there is a 25% chance that a child will be affected, a 50% chance that the child will be a carrier, and a 25% chance that the child will not carry the mutation at all. (Bidichandani and Delatycki 1993)

Siblings of a person with FA have a 25% chance themselves of having FA, a 50% chance of being a carrier, and a 25% chance of having no mutation.

References

 

 

Copyright August 3, 2016 , Timothy C. Hain, M.D. All rights reserved. Last saved on August 3, 2016